Treatment of gout

ABSTRACT

Sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio) acetate is described. In addition, pharmaceutical compositions and uses such compositions for the treatment of a variety of diseases and conditions.

CROSS-REFERENCE

This application is a continuation of the U.S. patent application Ser.No. 13/637,343, filed Oct. 24, 2012, which is a U.S. National Stageentry of International Application No. PCT/US11/30364, filed Mar. 29,2011, which claims priority to U.S. Provisional Application 61/319,014,filed Mar. 30, 2010, all of which are incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to the treatment of gout whilesubstantially reducing the duration and frequency of gout flaresassociated with reductions of uric acid levels.

BACKGROUND OF THE INVENTION

Gout is associated with elevated levels of uric acid that crystallizeand deposit in joints, tendons, and surrounding tissues. Gout is markedby recurrent attacks of red, tender, hot, and/or swollen joints.

SUMMARY OF THE INVENTION

The treatment of gout typically involves the reduction of serum uricacid levels. However, gout flares are associated with the reduction ofuric acid levels. Drugs such as colchicine can reduce the painassociated with gout flares while a patient's serum uric acid levels arebeing reduced, however, colchicine is associated with several undesiredside effects, including gastrointestinal disorders.

Accordingly, described herein are methods, compositions and dosingregimens for reducing serum uric acid levels while providing for aconcomitant reduction in the intensity and duration of gout flaresassociated with other gout medications. Furthermore, described hereinare methods, compositions and dosing regimens for weaning a patient offof co-administered colchicine; such weaning includes lower doses ofcolchicine and less time on colchicine relative to other goutmedications.

One embodiment provides a method of treating gout comprisingco-administration of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, and colchicine to asubject, wherein said method provides greater mean gout flare reductionthan co-administration of colchicine and therapeutic agent that is not adual inhibitor of URAT1 and an inflammasome.

Another embodiment provides the method wherein the total dosage ofcolchicine administered during co-administration with2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is at least 50% less thanthe total dosage of colchicine co-administered with a therapeutic agentthat is not a dual inhibitor of URAT1 and an inflammasome.

Another embodiment provides the method wherein the amount of time thatcolchicine is co-administered with2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is at least one week lessthan when colchicine is co-administered with a therapeutic agent that isnot a dual inhibitor of URAT1 and an inflammasome.

One embodiment provides a method of reducing the duration of gout flarescomprising administration of a pharmaceutical composition comprising2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, to a subject, wherein themean duration of the gout flares in a patient undergoing uric acid levelreduction is less than four days. Another embodiment provides themethod, wherein the mean duration of the gout flares is less than threedays. Another embodiment provides the method wherein the mean durationof the gout flares is less than two days.

One embodiment provides a method for treating gout comprisingadministration to a patient in need a therapeutic agent that is a dualinhibitor of URAT1 and inflammasome. Another embodiment provides themethod wherein the dual inhibitor of URAT1 and inflammasome is2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a polymorph thereof, or a pharmaceutically acceptable salt of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateor a polymorph thereof.

One embodiment provides a method of reducing monosodium urate inducedinflammation comprising administering a pharmaceutical compositioncomprising a pharmaceutical agent having both uricosuric andanti-inflammatory activity. Another embodiment provides the methodwherein the pharmaceutical agent is a URAT1 inhibitor withanti-inflammatory activity. Another embodiment provides the methodwherein the pharmaceutical agent is2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof.

In another embodiment is provided the method wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 750 mg. Inanother embodiment is provided the method wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 600 mg. Inanother embodiment is provided the method wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 500 mg. Inanother embodiment is provided the method wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 400 mg. Inanother embodiment is provided the method wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 200 mg.

In another embodiment is provided the method wherein the daily dose isadministered orally. In another embodiment is provided the methodwherein the daily dose is administered in the morning. In anotherembodiment is provided the method wherein the daily dose is administeredwith food.

Another embodiment provides the above listed methods of reducing theduration of gout flares further comprising administration of a secondserum uric acid lowering agent. In another embodiment is provided themethod wherein the second serum uric acid lowering agent is a xanthineoxidase inhibitor. In another embodiment is provided the method whereinthe xanthine oxidase inhibitor is febuxostat or allopurinol.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference for the purposes cited.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 illustrates the effect of Lesinurad on IL-1β release within 1hour of stimulation with ATP (5 mM) or 1 μg MSU (monosodium urate)crystals (compd1=Lesinurad; C-1inh=caspase-1 inhibitor).

FIG. 2A and FIG. 2B illustrate the effect of rilonacept (IL-1ra) onTNF-α (FIG. 2A) and IL-1β production (FIG. 2B).

FIG. 3A and FIG. 3B illustrate the effect of Lesinurad on TNF-α (FIG.3A) and IL-1β (FIG. 3B) production in differentiated THP-1 cells

FIG. 4A and FIG. 4B illustrate the effect of Lesinurad on IL-Iβ (FIG.4A) and the CLU count in a CellTiter-Glo® assay (FIG. 4B).

FIG. 5A and FIG. 5B illustrate the effect of Lesinurad (Comp1) in a ratmodel of inflammation in comparison with 1 mg/kg colchicine (FIG. 5A)and 0.1 mg/kg colchicine (FIG. 5B).

FIG. 6A, FIG. 6B and FIG. 6C illustrate in vivo MSU-induced inflammationin a rat air pouch study for various doses of Lesinurad p.o. (0.1, 1, 10mg/kg/day), colchicine s.c. (0.01, 0.1, 1 mg/kg), and Lesinurad andcolchicine (* indicates p<0.05 versus vehicle). FIG. 6A illustratesplasma extravasation value, FIG. 6B exudate volume, and FIG. 6C totalwhite blood cell count.

FIG. 7 illustrates the average increase in knee diameter (mm) in an invivo MSU-induced rat knee joint study for various doses of colchicines.c. (0.1, 0.3, 1 mg/kg), Lesinurad p.o. (60 mg/kg/day), and Lesinuradand colchicine (** indicates p<0.01 versus vehicle; *** indicatesp<0.001 versus vehicle).

FIG. 8 illustrates the Phase II clinical study design for Lesinuradtreatment of gout patients with hyperuricemia.

FIG. 9 illustrates the time to first flare compared to a publishedcolchicine control. The actual dose at the time of flare is shown andonly flares requiring treatment were considered.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, without limitation, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference in their entirety for any purpose.

The treatment of gout typically involves the reduction of serum uricacid levels. However, gout flares are associated with the reduction ofuric acid levels. Drugs such as colchicine can reduce the painassociated with gout flares while a patient's serum uric acid levels arebeing reduced, however, colchicine is associated with several undesiredside effects, including gastrointestinal disorders.

Accordingly, described herein are methods, compositions and dosingregimens for reducing serum uric acid levels while providing for aconcomitant reduction in the intensity and duration of gout flaresassociated with other gout medications. Furthermore, described hereinare methods, compositions and dosing regimens for weaning a patient offof co-administered colchicine; such weaning includes lower doses ofcolchicine and less time on colchicine relative to other goutmedications.

One embodiment provides a method of treating gout comprisingco-administration of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, and a second therapeuticagent for the treatment of gout (and/or symptoms thereof). In specificembodiments, the second therapeutic agent for the treatment of gout(and/or symptoms thereof) is an NSAID, steroid, or colchicine. In otherembodiments, the second therapeutic agent for the treatment of gout(and/or symptoms thereof) is any therapeutic agent described herein forthe treatment of gout (and/or symptoms thereof). In some embodiments,the second therapeutic agent for the treatment of gout (and/or symptomsthereof) is an agent that treats, reduces the intensity of, or reducesthe duration of gout symptoms (e.g., effects associated with gout otherthan uric acid concentrations). In specific embodiments, the secondagent is colchicine. In certain embodiments, provided herein is a methodof treating gout in a subject in need thereof, the method comprisingco-administering2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, and colchicine to asubject. In specific embodiments, provided herein is a method thatprovides greater mean gout flare reduction (intensity, incidences and/orduration) than co-administration of colchicine (e.g., a similar amountof colchicine) and therapeutic agent that is not a dual inhibitor ofURAT1 and an inflammasome. In some embodiments, a therapy describedherein is administered to a subject that has received previous gouttherapy comprising the administration of the second agent and a thirdtherapeutic agent for the treatment of gout (e.g., wherein the thirdtherapeutic agent is not an inhibitor of URAT1, is not an inflammasome,or both). In specific embodiments, the amount of second agent is reducedby at least 25%, at least 40%, at least 50%, at least 60%, at least 75%,or any other suitable amount when compared to the amount of second agentthat was administered with the third therapeutic agent.

Another embodiment provides the method wherein the total dosage ofcolchicine administered during co-administration with2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is at least 50% less thanthe total dosage of colchicine co-administered with a therapeutic agentthat is not a dual inhibitor of URAT1 and an inflammasome (e.g., atleast 50% less than the total dosage of colchicine that would berequired to provide a similar or identical effect when co-administeredwith a therapeutic agent that is not a dual inhibitor of URAT1 and aninflammasome; e.g., a similar effect being one wherein the effect is atleast 80% similar, at least 90% similar, or the like). In certainembodiments, the daily dosage of colchicine is less than 3 mg, less than1.5 mg, less than 1.2 mg, less than 1 mg, less than 0.7 mg, less than0.5 mg, less than 0.3 mg, or the like. In some embodiments, the initialdosage of colchicine is less than 1.2 mg, less than 1 mg, less than 0.7mg, less than 0.5 mg, less than 0.3 mg, or the like. In certainembodiments, the dosage of colchicine subsequent to the initial dose isless than 0.6 mg, less than 0.5 mg, less than 0.3 mg, less than 0.15 mg,or the like.

Another embodiment provides the method wherein the amount of time thatcolchicine is co-administered with2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is at least one week lessthan when colchicine is co-administered with a therapeutic agent that isnot a dual inhibitor of URAT1 and an inflammasome (e.g., at least oneweek less than the total dosage of colchicine that would be required toprovide a similar or identical effect when co-administered with atherapeutic agent that is not a dual inhibitor of URAT1 and aninflammasome; e.g., a similar effect being one wherein the effect is atleast 80% similar, at least 90% similar, or the like).

In some embodiments, provided herein is a method of treating goutcomprising administering to an individual in need thereof atherapeutically effective amount of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof. In specific embodiments,the therapeutically effective amount of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof is sufficient to reducethe incidences of, reduce the duration of, and/or reduce the severity orintensity of the gout symptoms (e.g., flares). In some embodiments, themethod further comprises reducing the amount of a second therapeuticagent for the treatment of gout, (and/or symptoms thereof), administeredto the subject. In some embodiments, the second therapeutic agent is anNSAID, steroid, or colchicine. In specific embodiments, the second agentis colchicine. In specific embodiments, the amount of second agent isreduced by at least 25%, at least 40%, at least 50%, at least 60%, atleast 75%, or any other amount to provide efficacious gout (and/or goutsymptom) therapy.

One embodiment provides a method of reducing the duration of gout flarescomprising administration of a pharmaceutical composition comprising2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, to a subject, wherein themean duration of the gout flares in a patient undergoing uric acid levelreduction is less than four days. Another embodiment provides themethod, wherein the mean duration of the gout flares is less than threedays. Another embodiment provides the method wherein the mean durationof the gout flares is less than two days.

One embodiment provides a method for treating gout comprisingadministration to a patient in need a therapeutic agent that is a dualinhibitor of URAT1 and inflammasome. Another embodiment provides themethod wherein the dual inhibitor of URAT1 and inflammasome is2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a polymorph thereof, or a pharmaceutically acceptable salt of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateor a polymorph thereof.

One embodiment provides a method of reducing monosodium urate inducedinflammation comprising administering a pharmaceutical compositioncomprising a pharmaceutical agent having both uricosuric andanti-inflammatory activity. Another embodiment provides the methodwherein the pharmaceutical agent is a URAT1 inhibitor withanti-inflammatory activity. Another embodiment provides the methodwherein the pharmaceutical agent is2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof.

In some embodiments a method described herein provides a daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 10 mg to about 2g, about 50 mg to about 1 g, about 200 mg to about 800 mg, about 200 mgto about 600 mg, or any other suitable therapeutically effective amount.In another embodiment is provided the method wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 750 mg. Inanother embodiment is provided the method wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 600 mg. Inanother embodiment is provided the method wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 500 mg. Inanother embodiment is provided the method wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 400 mg. Inanother embodiment is provided the method wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 200 mg.

In another embodiment is provided the method wherein the daily dose isadministered orally. In another embodiment is provided the methodwherein the daily dose is administered in the morning. In anotherembodiment is provided the method wherein the daily dose is administeredwith food.

Another embodiment provides the above listed methods of reducing theduration of gout flares further comprising administration of a secondserum uric acid lowering agent. In another embodiment is provided themethod wherein the second serum uric acid lowering agent is a xanthineoxidase inhibitor. In another embodiment is provided the method whereinthe xanthine oxidase inhibitor is febuxostat or allopurinol.

Gout

Gout is a painful form of arthritis caused by high uric acid in theblood (hyperuricemia). As serum uric acid (sUA) levels increase, so doesthe risk of having gout and painful flares. Decreasing uric acid to alevel of less than 6 mg/dL has been shown to be effective for managementof gout over the long-term.

According to the National Health and Nutrition Examination Survey III,1988-1994, an estimated 5.1 million people in the United States sufferfrom gout. Gout is the most common form of inflammatory arthritis inmen. Gout affects approximately 3 times as many men as women, and menare more likely than women to have gout at all ages. Racial and ethnicdifferences are not as distinct among patients in the US, though AfricanAmericans aged 45 years or older are more likely to have gout thanCaucasians in the same age group.

Gout flares occur when excess uric acid forms crystals, causinginflammation in the joints that leads to swelling and pain. Flareshappen most often in the toes, but can happen in hands, elbows, andknees. Gout flares often occur without warning and can cause jointswelling, severe pain, tenderness, redness, and heat. Over time, goutflares become more frequent and of greater duration.

Acute gout is caused by an inflammatory response to monosodium uratemonohydrate (MSUM) crystal formation—a temperature-dependent phenomenon,which can occur under conditions of elevated serum urate concentration.Gout flare is known as one of the most painful conditions inrheumatology, with pain intensity comparable to childbirth or long bonefractures. The condition regularly interrupts sleep, inhibits walking,and interferes with work and leisure activities.

Serum urate, produced when purines are metabolized, is eliminated fromthe body in the form of uric acid. Uric acid may have a significantphysiological function, acting as an antioxidant, a role in which it isas effective as ascorbate. However, when the balance of purinenucleotide synthesis, breakdown and recycling, and elimination becomesunbalanced, hyperuricemia may result.

The development of hyperuricemia is straightforward: uric acid builds upin the blood when the body increases its production of uric acid, or thekidneys do not eliminate it efficiently, or both. Overproduction isresponsible for 10% of cases of primary gout; underexcretion for 90%.

Production may increase through endogenous (cell turnover andmetabolism) and/or exogenous (dietary) factors.

Reduced elimination suggests a renal cause because most uric acid iseliminated via the kidneys. (Enteric elimination is the next mostsignificant means of elimination, and it can increase in response tohyperuricemia.) Genetic factors may play a role for individuals withhyperuricemia and reduced renal clearance of uric acid. Most subjectswith gout have lower clearance rates for uric acid, which may bemeasured directly or as a ratio of urate to inulin clearance(Curate/Cinulin ratio). However, most gout and hyperuricemia patientsshow no other renal function abnormality.

Though 90% of primary gout cases are triggered by difficulties in urateelimination, the exact mechanism behind lower uric acid clearance rateshas not been established. Known factors that may affect urate clearanceinclude the volume of urine flow (excretion is increased by >25% ifurine flow is doubled), the level of estrogens (as evidenced by lowerserum uric acid concentrations in women before menopause and inchildren), surgery, and autonomic nervous system function.

Secondary gout can also be attributed to a reduction in the glomerularfiltration rate causing a decrease in the excretion of uric acid by thekidney. This can be seen in certain kidney disorders or with medicationssuch as diuretics that interfere with urate excretion.

Gout Flares

The serum urate saturation point is approximately 6.8 mg/dL. Althoughseveral biochemical factors impact whether an individual experiences aflare at this point. Risk for the development of gout symptoms increasessteadily at concentrations higher than 6 mg/dL. In a patient withhyperuricemia, urate can crystallize as monosodium urate monohydrate(MSUM) and may form deposits in the synovial membrane. An acute goutattack can occur when there is a marked inflammatory response to thesecrystal deposits.

In broad terms, gout attacks are symptoms of the inflammatory responseto monosodium urate crystal deposition. Supersaturation of serum urateis the underlying cause, but not sufficient in and of itself to causeprecipitation. Similarly, the presence of crystals alone may beinsufficient to elicit an inflammatory response.

Asymptomatic patients may have crystals in the synovial fluid andneutrophils within the synovium—diagnostic clinical signs of gout.Additionally, microtophi have been identified in areas of the synoviumduring the early stages of gout attacks. These observations areconsistent with a continuum of inflammatory response betweenintercritical periods and acute attacks in chronic gout.

The inflammatory response may be initiated when microcrystals shed frommicrotophi adjacent to the joint space and enter the synovial fluid. Inaddition to their location, the size of the crystals may be asignificant factor. New microcrystals that form and those that break offfrom larger crystals appear to be essential to the process. Thisobservation may also explain why aggressive antihyperuricemic therapymay trigger a mobilization flare: it can cause larger crystals todissolve and release microcrystals. Thus, prophylactic treatment withanti-inflammatory drugs has been recommended for 6 months or longerafter the start of antihyperuricemic therapy, while urate levels are influx.

Many biochemical mediators are involved in the inflammatory response.Monocytes play a large role, releasing proinflammatory cytokines andattracting neutrophils to the site, thus amplifying the response.Phagocytes resident within the synovium may be insufficient to triggeran immune response to microcrystals. However, the entry of new monocytesand neutrophils may shift the immune balance, leading to the gout flare.

Treatment of Gout NSAIDs

NSAIDS are the usual first line treatment for gout with no significantdifference between agents in effectiveness. Improvement may be seenwithin 4 hours. They however are not recommended in those with certainother health problems such as gastrointestinal bleeding, renal failure,or heart failure. While indomethacin is historically the most commonlyused NSAID, due to concerns of side effects and no evidence of greaterbenefit, an alternative like ibuprofen may be preferred. For those atrisk of gastric irritation from NSAIDs, an additional proton pumpinhibitor may be given. NSAIDs include but are not limited toaminoarylcarboxylic acid derivatives such as enfenamic acid,etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamicacid, niflumic acid, talniflumate, terofenamate, and tolfenamic acid;arylacetic acid derivatives such as aceclofenac, acemetacin, alclofenac,amfenac, amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac,diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac,glucametacin, ibufenac, indomethacin, isofezolac isoxepac, lonazolac,metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin,sulindac, tiaramide, tolmetin, tropesin, and zomepirac; arylbutyric acidderivatives such as bumadizon, butibufen, fenbufen, xenbucin;arylcarboxylic acids such as clidanac, ketorolac, tinoridine;arylpropionic acid derivatives such as alminoprofen, benoxaprofen,bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen,flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen,naproxen, oxaprozin, piketoprofin, pirprofen, pranoprofen, protizinicacid, suprofen, tiaprofenic acid, ximoprofen, and zaltoprofen; pyrazolessuch as difenamizole, and epirozole; pyrazolones such as apazone,benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone,phenylbutazone, pipebuzone, propyphenazone, prostaglandins,ramifenazone, suxibuzone, and thiazolinobutazone; salicylic acidderivatives such as acetaminosalol, aspirin, benorylate, bromosaligenin,calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisicacid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate,mesalamine, morpholine salicylate, 1-naphtyl salicylate, olsalazine,parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide,salicylamide o-acetic acid, salicylsulfuric acid, salsalate,sulfasalazine; thiazinecarboxamides such as ampiroxicam, droxicam,isoxicam, lomoxicam, piroxicam, and tenoxicam; cyclooxygenase-IIinhibitors (“COX-II”) such as Celebrex (Celecoxib), Vioxx, Relafen,Lodine, and Voltaren and others, such as epsilon-acetamidocaproic acid,s-adenosylmethionine, 3-amino-4-hydroxybutytic acid, amixetrine,bendazac, benzydamine, α-bisabolol, bucololome, difenpiramide, ditazol,emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol,paranyline, perisoxal, proquazone, tenidap and zilenton; sleep aidsincluding but not limited to a benzodiazepine hypnotic,non-benzodiazepine hypnotic, antihistamine hypnotic, antidepressanthypnotic, herbal extract, barbiturate, peptide hypnotic, triazolam,brotizolam, loprazolam, lormetazepam, flunitrazepam, flurazepam,nitrazepam, quazepam, estazolam, temazepam, lorazepam, oxazepam,diazepam, halazepam, prazepam, alprazolam, chlordiazepoxide,clorazepate, an imidazopyridine or pyrazolopyrimidine hypnotic, zolpidemor zolpidem tartarate, zopiclone, eszopiclone, zaleplon, indiplone,diphenhydramine, doxylamine, phenyltoloxamine, pyrilamine, doxepin,amtriptyline, trimipramine, trazodon, nefazodone, buproprion,bupramityiptyline, an herbal extract such as valerian extract oramentoflavone, a hormone such as melatonin, or gabapeptin.

Steroids

Glucocorticoids have been found to be equally effective to NSAIDs andmay be used if contraindications exist for NSAIDs. Intra-articularsteroids have also been found to be effective however the risk ofconcurrent joint infection must be ruled out.

Colchicine

Colchicine is an alternative for those unable to tolerate NSAIDs. Itsside effects (primarily gastrointestinal upset) has decreased its usage.Gastrointestinal upset however depends on the dose and the risk can bedecreased by using smaller yet still effective doses. Colchicine mayinteract with other commonly prescribed drugs such as atorvastatin anderythromycin among others. When administered in the formulation marketedas COLCRYS (cholchicine, USP), the recommended dose for the prophylaxisof gout flares is 0.6 mg once or twice daily. For the treatment of goutflares the recommended dose is 1.2 mg at first indication of a flarefollowed by 0.6 mg one hour later.

Agents which have found use in the treatment of gout are P2x receptorinhibitors, reactive oxygen species inhibitors, toll like receptorantagonists, IL1 inhibitors—anakinra, rilonacept, TNF blockers—enbreletc., glucocorticoids prednisone, prednisolone, triamcinolone,dexamethasone, inflammasome inhibitors, caspase inhibitors,NSAIDS—celecoxib, Ibuprofen, naproxen, fenbufen, fenoprofen,flur-biprofen, ketoprofen, tiaprofenic acid, azapropazone, diclofenac,diflunisal, etodolac, indomethacin (indometacin), ketorolac, mefenamic,meloxicam, nabumetone, phenylbutazone, piroxicam, sulindac, tenoxicam,tolfenamic acid, hydroxychloroquine (Plaquenil) or chloroquine (Aralen),leflunomide (Arava), methotrexate, sulfasalazine azulfidine, Abatacept(Orencia), Adalimumab (Humira), Anakinra (Kineret), Etanercept (Enbrel),Infliximab (Remicade), Rituximab (Rituxan).

URAT1

URAT1 is a urate transporter and urate-anion exchanger which regulatesthe level of urate in the blood. This protein is an integral membraneprotein primarily found in kidney.

Inflammasome

The inflammasome is responsible for activation of inflammatoryprocesses, and has been shown to induce cell pyroptosis, a process ofprogrammed cell death distinct from apoptosis. The inflammasome is amultiprotein complex consisting of caspase 1, PYCARD, a NALP andsometimes caspase 5 or caspase 11. The exact composition of aninflammasome depends on the activator which initiates inflammasomeassembly i.e. dsRNA will trigger one inflammasome composition whereasasbestos will assembly a different variant. The inflammasome promotesthe maturation of inflammatory cytokines interleukin 143 and interleukin18.

The present invention relates to methods for treating or preventingdiseases, comprising administering an effective amount of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate.

Sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate

Sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetateis known to decrease uric acid levels, (see for example US 2009-0197825,U.S. patent application Ser. No. 12/553,844 and U.S. patent applicationSer. No. 12/554,719). Details of clinical studies involving sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetatehave been described in U.S. provisional patent application 61/252,530,U.S. provisional patent application 61/252,537 and U.S. provisionalpatent application 61/265,240.

Uric acid is the result of the oxidation of xanthine. Disorders of uricacid metabolism include, but are not limited to, polycythemia, myeloidmetaplasia, gout, a recurrent gout attack, gouty arthritis,hyperuricaemia, hypertension, a cardiovascular disease, coronary heartdisease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidneydisease, kidney stones, kidney failure, joint inflammation, arthritis,urolithiasis, plumbism, hyperparathyroidism, psoriasis or sarcoidosis.

DEFINITIONS

The term “subject”, as used herein in reference to individuals sufferingfrom a disorder, and the like, encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

The terms “effective amount”, “therapeutically effective amount” or“pharmaceutically effective amount” as used herein, refer to an amountof at least one agent or compound being administered that is sufficientto treat or prevent the particular disease or condition. The result canbe reduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in a disease. An appropriate“effective” amount in any individual case may be determined usingtechniques, such as a dose escalation study.

Modulating URAT-1 Activity

The invention also relates to methods of modulating URAT-1 activity bycontacting URAT-1 with an amount of a polymorphic, crystalline ormesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein, sufficient to modulate the activity of URAT-1.Modulate can be inhibiting or activating URAT-1 activity. In someembodiments, the invention provides methods of inhibiting URAT-1activity by contacting URAT-1 with an amount of a polymorphic,crystalline or mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein, sufficient to inhibit the activity of URAT-1. Insome embodiments, the invention provides methods of inhibiting URAT-1activity in a solution by contacting said solution with an amount of apolymorphic, crystalline or mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein sufficient to inhibit the activity of URAT-1 in saidsolution. In some embodiments, the invention provides methods ofinhibiting URAT-1 activity in a cell by contacting said cell with anamount of a polymorphic, crystalline or mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein, sufficient to inhibit the activity of URAT-1 insaid cell. In some embodiments, the invention provides methods ofinhibiting URAT-1 activity in a tissue by contacting said tissue with anamount of a polymorphic, crystalline or mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein, sufficient to inhibit the activity of URAT-1 insaid tissue. In some embodiments, the invention provides methods ofinhibiting URAT-1 activity in blood by contacting the blood with anamount of a polymorphic, crystalline or mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein, sufficient to inhibit the activity of URAT-1 inblood. In some embodiments, the invention provides methods of inhibitingURAT-1 activity in plasma by contacting the plasma with an amount of apolymorphic, crystalline or mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein, sufficient to inhibit the activity of URAT-1 inplasma. In some embodiments, the invention provides methods ofinhibiting URAT-1 activity in an animal by contacting said animal withan amount of a polymorphic, crystalline or mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein sufficient to inhibit the activity of URAT-1 in saidanimal. In some embodiments, the invention provides methods ofinhibiting URAT-1 activity in a mammal by contacting said mammal with anamount of a polymorphic, crystalline or mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein sufficient to inhibit the activity of URAT-1 in saidmammal. In some embodiments, the invention provides methods ofinhibiting URAT-1 activity in a human by contacting said human with anamount of a polymorphic, crystalline or mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein, sufficient to inhibit the activity of URAT-1 insaid human.

Pharmaceutical Compositions

Described herein are pharmaceutical compositions comprising an effectiveamount of a polymorphic, crystalline or mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein. In some embodiments, the pharmaceuticalcompositions comprise an effective amount of a polymorphic, crystallineor mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein, and at least one pharmaceutically acceptablecarrier. In some embodiments the pharmaceutical compositions are for thetreatment of disorders. In some embodiments the pharmaceuticalcompositions are for the treatment of disorders in a mammal. In someembodiments the pharmaceutical compositions are for the treatment ofdisorders in a human. In some embodiments the pharmaceuticalcompositions are for the treatment or prophylaxis of disorders of uricacid metabolism. In some embodiments the pharmaceutical compositions arefor the treatment or prophylaxis of hyperuricemia. In some embodimentsthe pharmaceutical compositions are for the treatment or prophylaxis ofgout.

Modes of Administration, Formulations and Dosage Forms

Described herein are pharmaceutical compositions comprising apolymorphic, crystalline or mesophase form of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,as described herein. The compound, compound forms and compositionsdescribed herein may be administered either alone or in combination withpharmaceutically acceptable carriers, excipients or diluents, in apharmaceutical composition, according to standard pharmaceuticalpractice. Administration can be effected by any method that enablesdelivery of the compounds to the site of action. These methods include,though are not limited to delivery via enteral routes (including oral,gastric or duodenal feeding tube, rectal suppository and rectal enema),parenteral routes (injection or infusion, including intraarterial,intracardiac, intradermal, intraduodenal, intramedullary, intramuscular,intraosseous, intraperitoneal, intrathecal, intravascular, intravenous,intravitreal, epidural and subcutaneous), inhalational, transdermal,transmucosal, sublingual, buccal and topical (including epicutaneous,dermal, enema, eye drops, ear drops, intranasal, vaginal)administration, although the most suitable route may depend upon forexample the condition and disorder of the recipient. Those of skill inthe art will be familiar with administration techniques that can beemployed with the compounds and methods of the invention. By way ofexample only, the compounds, compound forms and compositions describedherein can be administered locally to the area in need of treatment, byfor example, local infusion during surgery, topical application such ascreams or ointments, injection, catheter, or implant, said implant madefor example, out of a porous, non-porous, or gelatinous material,including membranes, such as sialastic membranes, or fibers. Theadministration can also be by direct injection at the site of a diseasedtissue or organ.

The pharmaceutical compositions described herein may, for example, be ina form suitable for oral administration as a tablet, capsule, pill,powder, sustained release formulations, solution, suspension, forparenteral injection as a sterile solution, suspension or emulsion, fortopical administration as an ointment or cream or for rectaladministration as a suppository. The pharmaceutical composition may bein unit dosage forms suitable for single administration of precisedosages. The pharmaceutical composition will include a conventionalpharmaceutical carrier or excipient and a compound according to theinvention as an active ingredient. In addition, it may include othermedicinal or pharmaceutical agents, carriers, adjuvants, etc.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing into association a compound orcompound form of the subject invention or a pharmaceutically acceptablesalt, ester, prodrug or solvate thereof (“active ingredient”) with thecarrier which constitutes one or more accessory ingredients. In general,the formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation. Methods of preparing various pharmaceuticalcompositions with a specific amount of active compound are known, orwill be apparent, to those skilled in this art.

Doses

The amount of pharmaceutical compositions administered will firstly bedependent on the mammal being treated. In the instances wherepharmaceutical compositions are administered to a human subject, thedaily dosage will normally be determined by the prescribing physicianwith the dosage generally varying according to the age, sex, diet,weight, general health and response of the individual patient, theseverity of the patient's symptoms, the precise indication or conditionbeing treated, the severity of the indication or condition beingtreated, time of administration, route of administration, thedisposition of the composition, rate of excretion, drug combination, andthe discretion of the prescribing physician. Also, the route ofadministration may vary depending on the condition and its severity. Thepharmaceutical composition may be in unit dosage form. In such form, thepreparation is subdivided into unit doses containing appropriatequantities of the active component, e.g., an effective amount to achievethe desired purpose. Determination of the proper dosage for a particularsituation is within the skill of the art. For convenience, the totaldaily dosage may be divided and administered in portions during the dayif desired. The amount and frequency of administration will be regulatedaccording to the judgment of the attending clinician (physician)considering such factors as described above. Thus the amount ofpharmaceutical composition to be administered may vary widely. Whenreferring to a dosage amount, the quantity stated is of the activepharmaceutical ingredient. Administration may occur in an amount ofbetween about 0.001 mg/kg of body weight to about 100 mg/kg of bodyweight per day (administered in single or divided doses), or at leastabout 0.1 mg/kg of body weight per day. A particular therapeutic dosagecan include, e.g., from about 0.01 mg to about 7000 mg of compound, or,e.g., from about 0.05 mg to about 2500 mg. The quantity of activecompound in a unit dose of preparation may be varied or adjusted fromabout 0.1 mg to 1000 mg, from about 1 mg to 300 mg, or 10 mg to 200 mg,according to the particular application. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, e.g. by dividing such largerdoses into several small doses for administration throughout the day. Incombinational applications in which the compound is not the soletherapy, it may be possible to administer lesser amounts of compound andstill have therapeutic or prophylactic effect.

Combination Therapies

The compounds and compound forms described herein may be administered asa sole therapy or in combination with another therapy or therapies.

By way of example only, if one of the side effects experienced by apatient upon receiving a compound or compound form as described hereinis hypertension, then it may be appropriate to administer ananti-hypertensive agent in combination with the compound. Or, by way ofexample only, the therapeutic effectiveness of a compound or compoundform as described herein may be enhanced by administration of anadjuvant (i.e., by itself the adjuvant may only have minimal therapeuticbenefit, but in combination with another therapeutic agent, the overalltherapeutic benefit to the patient is enhanced). Or, by way of exampleonly, the benefit experienced by a patient may be increased byadministering a compound or compound form as described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. Regardless of the disease, disorderor condition being treated, the overall benefit experienced by thepatient may simply be additive of the two therapeutic agents or thepatient may experience a synergistic benefit.

In the instances where the compounds or compound forms as describedherein are administered with other therapeutic agents, they need not beadministered in the same pharmaceutical composition as other therapeuticagents, and may, because of different physical and chemicalcharacteristics, be administered by a different route. For example, thecompound or compound form as described herein may be administered orallyto generate and maintain good blood levels thereof, while the othertherapeutic agent may be administered intravenously. The determinationof the mode of administration and the advisability of administration,where possible, in the same pharmaceutical composition, is well withinthe knowledge of the skilled clinician. The initial administration canbe made according to established protocols known in the art, and then,based upon the observed effects, the dosage, modes of administration andtimes of administration can be modified by the skilled clinician.

The compounds, compound forms and compositions described herein (andwhere appropriate other chemotherapeutic agent) may be administeredconcurrently (e.g., simultaneously, essentially simultaneously or withinthe same treatment protocol) sequentially or separately, depending uponthe nature of the disease, the condition of the patient, and the actualchoice of other chemotherapeutic agent to be administered. Forcombinational applications and uses, the compounds, compound forms andcompositions described herein and the chemotherapeutic agent need not beadministered simultaneously or essentially simultaneously. Thus, thecompounds, compound forms and compositions as described herein may beadministered first followed by the administration of thechemotherapeutic agent; or the chemotherapeutic agent may beadministered first followed by the administration of the compounds,compound forms and compositions as described herein. This alternateadministration may be repeated during a single treatment protocol. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the skilledphysician after evaluation of the disease being treated and thecondition of the patient. For example, the chemotherapeutic agent may beadministered first, especially if it is a cytotoxic agent, and then thetreatment continued with the administration of the compounds, compoundforms and compositions as described herein followed, where determinedadvantageous, by the administration of the chemotherapeutic agent, andso on until the treatment protocol is complete. Thus, in accordance withexperience and knowledge, the practicing physician can modify eachadministration protocol for treatment according to the individualpatient's needs, as the treatment proceeds. The attending clinician, injudging whether treatment is effective at the dosage administered, willconsider the general well-being of the patient as well as more definitesigns such as relief of disease-related symptoms. Relief ofdisease-related symptoms such as pain, and improvement in overallcondition can also be used to help judge effectiveness of treatment.

Specific, non-limiting examples of possible combination therapiesinclude use of the compounds and compositions described herein withFebuxostat, Allopurinol, Probenacid, Sulfinpyrazone, Losartan,Fenofibrate, Benzbromarone or PNP-inhibitors (such as, but not limitedto Forodesine, BCX-1777 or BCX-4208). This list should not be construedto be closed, but should instead serve as an illustrative example commonto the relevant therapeutic area at present. Moreover, combinationregimens may include a variety of routes of administration, includingbut not limited to oral, intravenous, intraocular, subcutaneous, dermal,and inhaled topical.

Diseases

Described herein are methods of treating a disease or disorder in anindividual suffering from said disease or disorder comprisingadministering to said individual an effective amount of a polymorph,crystalline form or mesophase as described herein of sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate.

The invention extends to the use of the compounds and compound formsdescribed herein in the manufacture of a medicament for treating adisease or disorder.

In some embodiments, the disease or disorder is hyperuricemia. Incertain instances, hyperuricemia is characterized by higher than normalblood levels of uric acid, sustained over long periods of time. Incertain instances, increased blood urate levels may be due to enhanceduric acid production (˜10-20%) and/or reduced renal excretion (˜80-90%)of uric acid. In certain instances, causes of hyperuricemia may includeobesity/weight gain, excessive alcohol use, excessive dietary purineintake (foods such as shellfish, fish roe, scallops, peas lentils, beansand red meat, particularly offal—brains, kidneys, tripe, liver), certainmedications, including low-dose aspirin, diuretics, niacin,cyclosporine, pyrazinamide, ethambutol, some high blood pressure drugsand some cancer chemotherapeutics, immunosuppressive and cytotoxicagents, specific disease states, particularly those associated with ahigh cell turnover rate (such as malignancy, leukemia, lymphoma orpsoriasis), and also including high blood pressure, hemoglobin diseases,hemolytic anemia, sickle cell anemia, various nephropathies,myeloproliferative and lymphoproliferative diseases,hyperparathyroidism, renal disease, conditions associated with insulinresistance and diabetes mellitus, and in transplant recipients, andpossibly heart disease, inherited enzyme defects, abnormal kidneyfunction (e.g. increased ATP turn over, reduced glomerular uratefiltration) and exposure to lead (plumbism or “saturnine gout”).

In certain instances, hyperuricemia may be asymptomatic, though isassociated with the following conditions: gout, gouty arthritis, uricacid stones in the urinary tract (urolithiasis), deposits of uric acidin the soft tissue (tophi), deposits of uric acid in the kidneys (uricacid nephropathy), and impaired kidney function, possibly leading tochronic and acute renal failure.

In further or additional embodiments, the disease or disorder is gout,which is a condition that results from uric acid crystals depositing intissues of the body. It is often related to an inherited abnormality inthe body's ability to process uric acid, but may also be exacerbated bya diet high in purines. Defective uric acid processing may lead toelevated levels of uric acid in the blood causing recurring attacks ofjoint inflammation (arthritis), uric acid deposits in and around thejoints, tophaceous gout, the formation of tophi, decreased kidneyfunction, and kidney stones. Approximately 3-5 million people in theUnited States suffer from attacks of gout with attacks 6 to 9 times morecommon in men than in women (see Sanders and Wortmann, “Harrison'sPrinciples of Internal Medicine”, 16th Edition; 2005; Food and DrugAdministration (FDA) Advisory Committee Meeting, Terkeltaubpresentation, June 2004; Terkeltaub, “Gout”, N Engl J Med., 349,1647-55, 2003). In certain instances, gout is one of the most commonforms of arthritis, accounting for approximately 5% of all arthritiscases. In certain instances, kidney failure and urolithiasis occur in10-18% of individuals with gout and are common sources of morbidity andmortality from the disease.

Gout is associated with hyperuricemia. In certain instances, individualssuffering from gout excrete approximately 40% less uric acid thannongouty individuals for any given plasma urate concentration. Incertain instances, urate levels increase until the saturation point isreached. In certain instances, precipitation of urate crystals occurswhen the saturation point is reached. In certain instances, thesehardened, crystallized deposits (tophi) form in the joints and skin,causing joint inflammation (arthritis). In certain instances, depositsare be made in the joint fluid (synovial fluid) and/or joint lining(synovial lining). Common areas for these deposits are the large toe,feet, ankles and hands (less common areas include the ears and eyes). Incertain instances, the skin around an affected joint becomes red andshiny with the affected area being tender and painful to touch. Incertain instances, gout attacks increase in frequency. In certaininstances, untreated acute gout attacks lead to permanent joint damageand disability. In certain instances, tissue deposition of urate leadsto: acute inflammatory arthritis, chronic arthritis, deposition of uratecrystals in renal parenchyma and urolithiasis. In certain instances, theincidence of gouty arthritis increases 5 fold in individuals with serumurate levels of 7 to 8.9 mg/dL and up to 50 fold in individuals withlevels >9 mg/dL (530 μmol/L). In certain instances, individuals withgout develop renal insufficiency and end stage renal disease (i.e.,“gouty nephropathy”). In certain instances, gouty nephropathy ischaracterized by a chronic interstitial nephropathy, which is promotedby medullary deposition of monosodium urate.

In certain instances, gout includes painful attacks of acute,monarticular, inflammatory arthritis, deposition of urate crystals injoints, deposition of urate crystals in renal parenchyma, urolithiasis(formation of calculus in the urinary tract), and nephrolithiasis(formation of kidney stones). In certain instances, secondary goutoccurs in individuals with cancer, particularly leukemia, and those withother blood diseases (e.g. polycythemia, myeloid metaplasia, etc).

In certain instances, attacks of gout develop very quickly, frequentlythe first attack occurring at night. In certain instances, symptomsinclude sudden, severe joint pain and extreme tenderness in the jointarea, joint swelling and shiny red or purple skin around the joint. Incertain instances, the attacks are infrequent lasting 5-10 days, with nosymptoms between episodes. In certain instances, attacks become morefrequent and last longer, especially if the disease is not controlled.In certain instances, episodes damage the affected joint(s) resulting instiffness, swelling, limited motion and/or persistent mild to moderatepain.

Plumbism or “saturnine gout,” is a lead-induced hyperuricemia thatresults from lead inhibition of tubular urate transport causingdecreased renal excretion of uric acid. In certain instances, more than50% of individuals suffering from lead nephropathy suffer from gout. Incertain instances, acute attacks of saturnine gout occur in the kneemore frequently than the big toe. In certain instances, renal disease ismore frequent and more severe in saturnine gout than in primary gout. Incertain instances, treatment consists of excluding the individual fromfurther exposure to lead, the use of chelating agents to remove lead,and control of acute gouty arthritis and hyperuricaemia. In certaininstances, saturnine gout is characterized by less frequent attacks thanprimary gout. In certain instances, lead-associated gout occurs inpre-menopausal women, an uncommon occurrence in non lead-associatedgout.

In certain instances, Lesch-Nyhan syndrome (LNS or Nyhan's syndrome)affects about one in 100,000 live births. In certain instances, LNS iscaused by a genetic deficiency of the enzyme hypoxanthine-guaninephosphoribosyltransferase (HGPRT). In certain instances, LNS is anX-linked recessive disease. In certain instances, LNS is present atbirth in baby boys. In certain instances, the disease leads to severegout, poor muscle control, and moderate mental retardation, which appearin the first year of life. In certain instances, the disease alsoresults in self-mutilating behaviors (e.g., lip and finger biting, headbanging) beginning in the second year of life. In certain instances, thedisease also results in gout-like swelling in the joints and severekidney problems. In certain instances, the disease leads neurologicalsymptoms include facial grimacing, involuntary writhing, and repetitivemovements of the arms and legs similar to those seen in Huntington'sdisease. The prognosis for individuals with LNS is poor. In certaininstances, the life expectancy of an untreated individual with LNS isless than about 5 years. In certain instances, the life expectancy of atreated individual with LNS is greater than about 40 years of age.

In certain instances, hyperuricemia is found in individuals withcardiovascular disease (CVD) and/or renal disease. In certain instances,hyperuricemia is found in individuals with prehypertension,hypertension, increased proximal sodium reabsorption, microalbuminuria,proteinuria, kidney disease, obesity, hypertriglyceridemia, lowhigh-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia,hypoadiponectinemia, peripheral, carotid and coronary artery disease,atherosclerosis, congestive heart failure, stroke, tumor lysis syndrome,endothelial dysfunction, oxidative stress, elevated renin levels,elevated endothelin levels, and/or elevated C-reactive protein levels.In certain instances, hyperuricemia is found in individuals with obesity(e.g., central obesity), high blood pressure, hyperlipidemia, and/orimpaired fasting glucose. In certain instances, hyperuricemia is foundin individuals with metabolic syndrome. In certain instances, goutyarthritis is indicative of an increased risk of acute myocardialinfarction. In some embodiments, administration of a compound describedherein to an individual are useful for decreasing the likelihood of aclinical event associated with a disease or condition linked tohyperuricemia, including, but not limited to, prehypertension,hypertension, increased proximal sodium reabsorption, microalbuminuria,proteinuria, kidney disease, obesity, hypertriglyceridemia, lowhigh-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia,hypoadiponectinemia, peripheral, carotid and coronary artery disease,atherosclerosis, congestive heart failure, stroke, tumor lysis syndrome,endothelial dysfunction, oxidative stress, elevated renin levels,elevated endothelin levels, and/or elevated C-reactive protein levels.

In some embodiments, a compound or compound form as described herein isadministered to an individual suffering from a disease or conditionrequiring treatment with a diuretic. In some embodiments, a compound orcompound form as described herein is administered to an individualsuffering from a disease or condition requiring treatment with adiuretic, wherein the diuretic causes renal retention of urate. In someembodiments, the disease or condition is congestive heart failure oressential hypertension.

In some embodiments, administration of a compound or compound form asdescribed herein to an individual is useful for improving motility orimproving quality of life.

In some embodiments, administration of a compound or compound form asdescribed herein to an individual is useful for treating or decreasingthe side effects of cancer treatment.

In some embodiments, administration of a compound or compound form asdescribed herein to an individual is useful for decreasing kidneytoxicity of cis-platin.

In certain instances, gout is treated by lowering the production of uricacid. In certain instances, gout is treated by increasing the excretionof uric acid. In certain instances, gout is treated by URAT 1, xanthineoxidase, xanthine dehydrogenase, xanthine oxidoreductase, a purinenucleoside phosphorylase (PNP) inhibitor, a uric acid transporter (URAT)inhibitor, a glucose transporter (GLUT) inhibitor, a GLUT-9 inhibitor, asolute carrier family 2 (facilitated glucose transporter), member 9(SLC2A9) inhibitor, an organic anion transporter (OAT) inhibitor, anOAT-4 inhibitor, or combinations thereof. In general, the goals of gouttreatment are to i) reduce the pain, swelling and duration of an acuteattack, and ii) prevent future attacks and joint damage. In certaininstances, gout attacks are treated successfully using a combination oftreatments. In certain instances, gout is one of the most treatableforms of arthritis.

i) Treating the Gout Attack.

In certain instances, the pain and swelling associated with an acuteattack of gout can be addressed with medications such as acetaminophen,steroids, nonsteroidal anti-inflammatory drugs (NSAIDs),adrenocorticotropic hormone (ACTH) or colchicine. In certain instances,proper medication controls gout within 12 to 24 hours and treatment isstopped after a few days. In certain instances, medication is used inconjunction with rest, increased fluid intake, ice-packs, elevationand/or protection of the affected area/s. In certain instances, theaforementioned treatments do not prevent recurrent attacks and they donot affect the underlying diseases of abnormal uric acid metabolism.

ii) Preventing Future Attacks.

In certain instances, reducing serum uric acid levels below thesaturation level is the goal for preventing further gout attacks. Insome cases, this is achieved by decreasing uric acid production (e.g.allopurinol), or increasing uric acid excretion with uricosuric agents(e.g. probenecid, sulfinpyrazone, benzbromarone).

In certain instances, allopurinol inhibits uric acid formation,resulting in a reduction in both the serum and urinary uric acid levelsand becomes fully effective after 2 to 3 months.

In certain instances, allopurinol is a structural analogue ofhypoxanthine, (differing only in the transposition of the carbon andnitrogen atoms at positions 7 and 8), which inhibits the action ofxanthine oxidase, the enzyme responsible for the conversion ofhypoxanthine to xanthine, and xanthine to uric acid. In certaininstances, it is metabolized to the corresponding xanthine analogue,alloxanthine (oxypurinol), which is also an inhibitor of xanthineoxidase. In certain instances, alloxanthine, though more potent ininhibiting xanthine oxidase, is less pharmaceutically acceptable due tolow oral bioavailability. In certain instances, fatal reactions due tohypersensitivity, bone marrow suppression, hepatitis, and vasculitishave been reported with Allopurinol. In certain instances, the incidenceof side effects may total 20% of all individuals treated with the drug.Treatment for diseases of uric acid metabolism has not evolvedsignificantly in the following two decades since the introduction ofallopurinol.

In certain instances, uricosuric agents (e.g., probenecid,sulfinpyrazone, and benzbromarone) increase uric acid excretion. Incertain instances, probenecid causes an increase in uric acid secretionby the renal tubules and, when used chronically, mobilizes body storesof urate. In certain instances, 25-50% of individuals treated withprobenecid fail to achieve reduction of serum uric acid levels <6 mg/dL.In certain instances, insensitivity to probenecid results from drugintolerance, concomitant salicylate ingestion, and renal impairment. Incertain instances, one-third of the individuals develop intolerance toprobenecid. In certain instances, administration of uricosuric agentsalso results in urinary calculus, gastrointestinal obstruction, jaundiceand anemia.

Successful treatment aims to reduce both the pain associated with acutegout flare and long-term damage to the affected joints (Emerson, “TheManagement of Gout”, N Engl J Med., 334(7), 445-451, 1996). Therapeuticgoals include providing rapid and safe pain relief, preventing furtherattacks, preventing the formation of tophi and subsequent arthritis, andavoiding exacerbating other medical conditions. Initiation of treatmentdepends upon the underlying causes of hyperuricemia, such as renalfunction, diet, and medications. While gout is a treatable condition,there are limited treatments available for managing acute and chronicgout and a number of adverse effects are associated with currenttherapies. Medication treatment of gout includes pain management,prevention or decrease in joint inflammation during an acute goutyattack, and chronic long-term therapy to maintain decreased serum uricacid levels.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effectiveanti-inflammatory medications for acute gout but are frequentlyassociated with irritation of the gastrointestinal (GI) system,ulceration of the stomach and intestines, and occasionally intestinalbleeding (Schlesinger, “Management of Acute and Chronic Gouty ArthritisPresent State-of-the-Art”; Medications; 64 (21), 2399-2416, 2004;Pascual and Sivera, “Therapeutic advances in gout”; Curr OpinRheumatol., March; 19(2), 122-7, 2007). Colchicine for acute gout ismost commonly administered orally as tablets (every 1-2 hours untilthere is significant improvement in pain or the patient develops GI sideeffects such as severe diarrhea, nausea and vomiting), or intravenously.Corticosteroids, given in short courses, can be administered orally orinjected directly into the inflamed joint.

Medications are available for reducing blood uric acid levels thateither increase renal excretion of uric acid by inhibiting re-uptake orreduce production of uric acid by blockade of xanthine oxidase. Thesemedicines are generally not initiated until after the inflammation fromacute gouty arthritis has subsided because they may intensify theattack. If they are already being taken prior to the attack, they arecontinued and only adjusted after the attack has resolved. Since manysubjects with elevated blood uric acid levels may not develop goutyattacks or kidney stones, the decision for prolonged treatment with uricacid-lowering medications is individualized.

Kits

The compounds, compound forms, compositions and methods described hereinprovide kits for the treatment of diseases and disorders, such as theones described herein. These kits comprise a compound, compound form,compounds, compound forms or compositions described herein in acontainer and, optionally, instructions teaching the use of the kitaccording to the various methods and approaches described herein. Suchkits may also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, or otherinformation useful to the health care provider. Such information may bebased on the results of various studies, for example, studies usingexperimental animals involving in vivo models and studies based on humanclinical trials. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits may also, in some embodiments,be marketed directly to the consumer.

The compounds, compound forms and pharmaceutical compositions describedherein may be utilized for diagnostics and as research reagents. Forexample, the compounds, compound forms and pharmaceutical compositions,either alone or in combination with other compounds, can be used astools in differential and/or combinatorial analyses to elucidateexpression patterns of genes expressed within cells and tissues. As onenon-limiting example, expression patterns within cells or tissuestreated with one or more compounds are compared to control cells ortissues not treated with compounds and the patterns produced areanalyzed for differential levels of gene expression as they pertain, forexample, to disease association, signaling pathway, cellularlocalization, expression level, size, structure or function of the genesexamined. These analyses can be performed on stimulated or unstimulatedcells and in the presence or absence of other compounds which affectexpression patterns.

Besides being useful for human treatment, the compounds, compound formsand pharmaceutical compositions described herein are also useful forveterinary treatment of companion animals (e.g. dogs, cats), exoticanimals and farm animals (e.g. horses), including mammals, rodents, andthe like.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations.

EXAMPLES Lesinurad

Lesinurad is the generic name for2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)aceticacid, whose chemical structure is:

In some instances, the term Lesinurad also includes the sodium salt ofLesinurad, i.e. sodium2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate.In the examples described herein, the compound administered may beLesinurad, or its sodium salt, in an amorphous or polymorph formthereof. In instances where the sodium salt is used, the amounts quotedherein may in fact be lower than the actual amounts of the sodium saltof Lesinurad used in the experiment, but were calculated to provide aneffective amount of the free acid compound.

I. In Vitro Experiments Example 1 Comparison of Lesinurad to Other GoutTherapies

Activation of the inflammasome results in the release of preformed IL-1,which goes on to activate other targets as well as increase theproduction of IL-1 itself. Lesinurad blocks IL-1 release very early,within 1 hour of stimulation, as illustrated in FIG. 1. This activitymay be compared with rilonacept which only inhibits the production ofTNF-α, (as expected since TNF-α production is downstream of IL-1βaction) as illustrated in FIG. 2A (6 hour time point). However,rilonacept does not reduce IL-1 production as illustrated in FIG. 2B.

Example 2 In Vitro MSU-Induced Inflammation to Assess the Effect ofLesinurad on Human Cells Example 2A In Vitro THP-1 (Human Cell) AssayStep A: Preparation of MSU Crystals

Uric acid (2 g, Sigma, Cat# U0881, Log S89329-419) was heated in a flaskat 200° C. for 2 hours. Endotoxin free water (396 mL) followed byaqueous sodium hydroxide solution (2.375 mL of 5N or 1.19 mL 10N) wereadded and heated on a stir plate until the uric acid dissolved. It wasthen cooled, filtered (stericup filter), and the pH measured (pH 7.9).The solution was stirred at room temperature for 24 hours and thencentrifuged at 1000 g for 10 min. The supernatant was discarded andresuspended in PBS and centrifuged at 1000 g for 10 min; this step wasrepeated twice. The washed crystals were heated at 60° C. until dry andthen autoclaved at 200° C. for 2 hours. The crystals were then weighedand resuspended in PBS at a concentration of 26 mg/ml.

Step B: Assay Details

THP-1 cells were differentiated with 0.5 μM of phorbol myristate acetate(PMA) incubated for 3 hours. Cells were then spun down and washed oncewith HBSS. 1.25×10⁶/mL cells were plated in white clear bottom white 96well plate in 100 μL volume and incubated overnight. The next day themedia was aspirated from the wells. 100 μl of 1× Optimem along with thecompounds were added. The cells and Lesinurad were incubated at 37° C.for 6 hours. 75 ul of the supernatant was collected and frozen to −20°C. for cytokine/chemokine analysis by MSD. 10 μL of CellTiter-Glo(Promega) was added to the assay plate and incubated at R.T for 15 minsand then read on analyst.

Step C: IL-1β and TNF-α

FIG. 3A shows a plot of Lesinurad concentration (log) versus TNF-αconcentration (pg/ml), generating a Lesinurad TNF-α IC₅₀ ˜52 uM. FIG. 3Bshows a plot of Lesinurad concentration (log) versus IL-1β concentration(pg/ml), generating a Lesinurad IL-1β IC₅₀ ˜30 uM.

Example 2B In Vitro Primary Human Monocyte Assay

Step A: Isolation of human Peripheral Blood Mononuclear Cells (hPBMCs)

Blood (50-60 ml) was collected in Heparin vaccutainers (BD vaccutainer,Cat No—367874, Sodium Heparin, 10 ml tube; each holding ˜8-10 ml blood),which was immediately mixed to prevent coagulation. Accuspin-Histopaque1077 (Sigma Aldrich cat no—A7054) was allowed to reach room temperatureand diluted blood 1:1 in DPBS (Dulbecco's Phosphate-Buffered Saline(1×), liquid—Invitrogen, 14040-133), mixed by pipetting. The tubes werecentrifuged (800 g; 30 seconds; room temp) to ensure all the Histopaque1077 was below the high density polyethylene barrier.

Diluted blood (50 ml) was added to the upper chamber of each ACCUSPINtube and centrifuged at room temp for 10 minutes at 1000×g or 15 minutesat 800×g, (brakes were off for this step; acc=1, dcl=1). PBMCs werecollected from the PBS/Ficoll interphase with a transfer pipette andtransferred to a new 50 mL tube. 10% RPMI was added to bring the volumeto 40 ml and the cells spun down at 240×g (1000 rpm), 8 min at roomtemp.

Supernatant was decanted and 5 mL of RBC lysis solution added to thepellet and mixed well. The tubes were incubated at room temp for 5 mins,diluted to 10 mL with DPBS and spun down at 240×g (1000 rpm), 8 min,room temp. The supernatant was discarded, resuspended in RPMI completemedia, and the cells counted.

Materials and Reagents:

-   -   RBC lysis buffer—Miltenyi Biotec Red Blood Cell Lysis Solution        (#130-094-183)    -   RPMI—RPMI Medium 1640 (1×), liquid Cat. No. 11875-135    -   FBS—Fetal Bovine Serum, Qualified, Heat-Inactivated Cat. No.        16140-071    -   10% RPMI—RPMI+10% FBS    -   DMSO—Opti-Freeze DMSO Cryopreservation Medium, Fisher        BioReagents, Cat NO BP2652-50    -   Freezing media—50% FBS+40% RPMI+10% DMSO

Step B: Isolation of Monocytes

The hPBM cells isolated in step A were counted, centrifuged (300 g; 10min) and the supernatant aspirated. The cell pellet was resuspended in80 ul of buffer per 10̂7 total cells, and 20 ul of CD14 Microbeads per10̂7 cells added and after mixing incubated on ice 15 mins. The cellswere washed by adding 5 ml of MACs buffer and centrifuged (300 g; 10mins).

While the cells were being centrifuged, the MACS MS column wasequilibrated by placing the column onto the magnet. 15 ml conical tubewas placed below the column to collect the flow through. 3 ml of MACSbuffer was added to the column to equilibrate it; flow through wasdiscarded and a new 15 ml tube placed under the column.

The centrifuged cells were then resuspended in 5 ml of MACS buffer andapplied to the column. The flow through was discarded. The column wasthen removed from the magnet and placed on a new 15 ml tube. 3 ml ofMACS buffer was added to the column and the flow through containing themonocytes collected. Cells were spun down (300 g, 5 min; supernatantdiscarded), resuspended in RPMI complete media and counted.

Materials and Reagents:

-   -   Miltenyi Bio's Monocyte Isolation kit II—Cat No—130-050-201    -   MACS buffer: PBS—pH 7.2 100 ml; 0.5% FBS; 2 mM EDTA    -   RPMI complete media recipe: 10% heat inactivated fetal bovine        serum    -   RPMI 1640: 1% PenStrepGlut; 1% Non-Essential Amino Acid; 1%        Hepes; 1% Na-pyruvate; BME    -   GPCR study performed by Life Technologies    -   Chemotaxis assay performed by Bio-quant (in primary human        monocytes, neutrophils and T cells).

Step C: IL-1β and CLU

FIG. 4A shows a plot of IL-1β (pg/ml) for varying concentrations ofLesinurad (100 uM, 50 uM and 25 uM), indicating dose dependent IL-1βinhibition with a Lesinurad an IL-1β IC₅₀ ˜50 uM. FIG. 4B shows a plotof CLU for varying concentrations of Lesinurad (100 uM, 50 uM and 25uM).

II In Vivo Rat Studies Example 3 Effect of Orally Administered Lesinuradon Monosodium Urate (MSU) Crystal-Induced Inflammation in Rats Example3A Effects of Lesinurad in a Rat Air Pouch Model of Crystal-InducedArthropathy

Procedure

-   -   1. Preparation of monosodium urate (MSU) crystals.        -   a. 1.68 g uric acid was dissolved in 500 ml 0.01 NaOH and            heated to 70° C. NaOH was added as required to maintain pH            8-9. The solution was filtered and incubated at ambient with            slow stirring continuously for 24 hours.        -   b. Crystals were washed, dried and sterilized by            autoclaving.        -   c. Crystals were suspended in sterile saline at 0.67 mg/ml,            2.67 mg/ml and 10 mg/ml just prior to use.    -   2. 110 Sprague-Dawley rats (male, 160-180 g) were quarantined        for 3 days; rats were accepted for the Study if no signs of        clinical distress were noted during the quarantine period. The        rats were maintained on certified laboratory diet and water ad        libitum.    -   3. The rats were ear-notched for individual identification and        rat weights were recorded.    -   4. The rats were distributed randomly to 11 groups of 10 rats        per group based upon average weight.    -   5. The rats were anesthetized and bled for sample from        retro-orbital sinus into microtainer tubes.        -   a. The blood was processed to serum;        -   b. The serum was transferred to labeled Eppendorf tubes            (T=0) and stored at −80° C.        -   c. Minimum serum volume of 100 μl (or 200 μl blood) was            collected from each rat.    -   6. DAY 0: The rats are anesthetized.        -   a. The nape of the neck was shaved, cleansed with 70%            isopropanol followed by cleansing with Povidone.        -   b. A 23-gauge needle was attached to a 30 ml syringe fitted            with an air filter.        -   c. 30 ml of sterile air was injected subcutaneously and the            rat returned to routine maintenance.    -   7. DAY 3: Steps 6a) through 6c) were repeated.    -   8. DAYS 4 and 5:        -   a. Rats in test compound groups were dosed once daily by            subcutaneous injection or oral dosing as in the treatment            table below.        -   b. 24 hours after dosing on DAY 4 (DAY 5), sample bleeds are            collected from each rat immediately prior to dosing on DAY            5, processed to serum and stored at −80° C. A minimum of            0.100 ml serum was collected for each bleed.    -   9. DAY 6: TIME=0 HOUR: Rats were injected subcutaneously with        Colchicine or dosed orally with Vehicle, Lesinurad or        Allopurinol.        -   Lesinurad formulation: Lesinurad was dissolved in distilled            water (dH₂O) to prepare a 20 mg/ml dosing solution (Group            10). The 20 mg/ml stock was diluted in dH₂O to prepare a 6            mg/ml solution (Group 9) and a 2 mg/ml solution (Group 8).        -   Allopurinol formulation: Allopurinol was dissolved in            distilled water (dH₂O) to prepare a 2 mg/ml dosing solution            (Group 11).        -   Immediately following SC injections, each animal was            injected intravenously with Evans blue dye (2.5% w/vol; 2.0            ml/kg). Evans blue binds to albumin and acts as a marker for            plasma extravasation.    -   10. Group Treatments are shown in Table 1.

TABLE 1 Group Treatment Schedule Dose Group No. Rats Treatment (mg/kg)ROA Timing MSU (mg) 1 10 Vehicle N/A PO −30 min None 2 10 Vehicle N/A PO−30 min 10 3 10 Vehicle N/A PO −30 min 40 4 10 Vehicle N/A PO −30 min150 5 10 Colchicine 0.01 SC −30 min 150 6 10 Colchicine 0.1 SC −30 min150 7 10 Colchicine 1 SC −30 min 150 8 10 Lesinurad 10 PO −30 min 150 910 Lesinurad 30 PO −30 min 150 10 10 Lesinurad 100 PO −30 min 150 11 10Allopurinol 10 PO −30 min 150

-   -   11. Thirty minutes after treatment, the rats were anesthetized        and injected into the air pouch with 15 ml MSU suspension.    -   12. Four (4) hours after MSU injection, the rats were        anesthetized and bled for sample from retro-orbital sinus into        microtainer tubes.        -   a. The blood was processed to serum        -   b. The serum was transferred to labeled Eppendorf tubes            (T=0) and stored at −80° C.        -   c. Minimum serum volume of 100 μl (or 200 μl blood) was            collected from each rat.        -   d. 5 ml sterile PBS containing 10 U/ml heparin injected into            the air pouch of anesthetized rats.    -   13. The pouch was gently massaged and the exudate was        immediately removed from the air pouch. Exudates volume was        measured and recorded for each animal.        -   a. Exudate cells were collected by centrifugation at 2,000            rpm for 5 minutes at room temperature. The supernatants were            aliquoted to two portions and stored at −80° C.        -   b. Cells were re-suspended in 0.5 ml heparinized saline for            neutrophil cell counts.        -   c. Plasma extravasation was measured by optical absorbance            at 620 nm for each exudate sample.    -   14. Exudate from each animal was assayed for TNF-alpha and IL-1.    -   15. Data treatments:        -   a. Mean cell counts and standard deviations were determined            for each group.        -   b. Mean optical absorbance measurements and standard            deviations were determined for each group.        -   c. Group means and standard deviations for TNF-alpha and            IL-1 were determined for each group.        -   d. Statistical significance of treatments on mean cell            counts, mean optical absorbance measurements and mean            cytokine measurements were determined by comparison of means            for treatment and positive control groups with vehicle            group.

Results

As shown in FIG. 5A and FIG. 5B, (total white blood cell counts for 10mg/kg, 30 mg/kg and 100 mg/kg Lesinurad) monosodium uratecrystal-induced inflammatory response was blocked by Lesinurad. FIG. 5Aprovides the comparison with 1 mg/kg colchicine. FIG. 5B provides thecomparison with 0.1 mg/kg colchicine.

Example 3B In Vivo MSU-Induced Inflammation—Rat Air Pouch Study

The objective of this study was to assess the effect of Lesinurad (dosedorally, 0.1-60 mg/kg QD) in monosodium urate (MSU) crystalinjection-induced inflammation in rats.

Step A: Animals and Animal Care

Male Sprague-Dawley rats weighing 130-200 g from Harlan, Indianapolis,Ind. (Air Pouch studies) were unpacked, placed in cages, a healthinspection performed and a number assigned. Rats were caged in groups of3-5 with free access to certified laboratory rodent chow and drinkingwater, in environmentally-controlled rooms (20-26° C.; 40-70% relativehumidity), with time-controlled fluorescent lighting systems providing12/12 dark light cycle.

Step B: Method

Under anesthesia, 30 mL sterile air was injected subcutaneously on day 0and day 3. Vehicle (water) or Lesinurad were administered orally. On theday of the experiment, rats were dosed with Vehicle, Lesinurad p.o.,and/or colchicine s.c. (Sigma, Cat. #C9754, Lot. #188K1131). Immediatelyfollowing administrations, each animal was injected i.v. with Evans bluedye (2.5% w/vol; 2.0 ml/kg), which binds to albumin and acts as a plasmaextravasation marker. 30 min post drug administration, the rats wereanesthetized and the air pouch injected with 15 ml of either saline orMSU suspension (10 mg/mL). Four (4) hours after MSU injection, 5 ml ofsterile PBS containing 10 U/ml heparin was injected into the air pouchof anesthetized rats. The pouch was gently massaged and the exudate wasimmediately removed from the air pouch. The exudate volume was measuredand recorded for each animal. Cells in the exudate were collected bycentrifugation (2,000 rpm; 5 mins; rt). The supernatants were stored at−20° C. for cytokine analysis. Cells were re-suspended in 0.5 mlheparinized saline for neutrophil cell counts. Plasma extravasation wasmeasured by optical absorbance at 620 nm for each exudate sample. Bloodsample bleeds were collected from each animal to provide 0.5 ml minimumvolume of serum per rat.

Step C: Extravasation (Optical Absorbance at 620 nm)

Extravasation values for various doses of Lesinurad and/or colchicineare shown in Table 2 below and in FIG. 6A, demonstrating:

-   -   Saline injection (no MSU) produces no detectable extravasation;    -   MSU crystal injection induces extravasation;    -   Colchicine (0.01, 0.1 and 1 mg/kg) showed a dose-dependent        decrease in extravasation;    -   Lesinurad (10 mg/kg) reduced extravasation.

TABLE 2 Extravasation Values for Various Doses of Lesinurad and/orColchicine Dose Regimen mg/kg 1 2 3 4 5 6 7 8 9 10 Av ¹Control — 0.00−0.01 0.00 0.00 −0.01 −0.01 −0.02 −0.01 0.00 −0.01 −0.01 ²Vehicle — 2.161.42 1.68 1.94 1.66 1.80 1.76 1.89 2.11 1.62 1.80 Colchicine 0.01 1.461.67 1.63 1.74 2.62 2.39 1.99 1.42 1.34 1.53 1.78 0.1 1.31 1.74 0.681.75 1.72 0.98 0.83 1.22 1.25 1.41 1.29 1 1.17 1.19 1.24 1.24 1.12 0.520.73 0.59 0.75 0.36 0.89 Lesinurad 0.1 1.89 2.19 1.54 2.14 1.94 1.611.90 1.88 1.84 1.83 1.87 1 2.27 1.36 1.94 1.67 1.79 1.98 2.04 1.83 1.792.01 1.87 10 0.89 0.77 0.71 0.97 0.82 1.94 0.82 1.25 1.20 0.93 1.03Lesinurad/ 10/0.01 0.71 1.24 1.04 1.08 0.78 0.70 1.23 0.70 0.84 1.510.98 Colchicine 10/0.1  0.82 1.06 1.07 1.11 1.21 1.36 1.31 1.35 1.630.43 1.13 ¹Control = no MSU; ²Vehicle = sterile saline

Step D: Exudate Volume

Exudate volume values (mL) for various doses of Lesinurad and/orcolchicine are shown in Table 3 below and in FIG. 6B, demonstrating:

-   -   In vehicle-treated rats, the amount of exudate more than doubles    -   At 0.01 and 0.1 mg/kg doses colchicine did not significantly        reduce exudate volume.    -   At 1 mg/kg colchicine significantly reduced exudate volume.    -   At 0.1 and 1 mg/kg/day doses Lesinurad 1 did not significantly        reduce exudate volume.    -   At 10 mg/kg/day Lesinurad significantly reduced exudate volume.    -   Lesinurad 10 mg/kg/day co-administered with colchicine (0.01 and        0.1 mg/kg), did not significantly reduce exudate volume better        than either therapy alone.    -   A number of cytokines in the exudates were measured; Lesinurad        significantly reduced IL-4 levels.

TABLE 3 Exudate Volume Values for Various Doses of Lesinurad and/orColchicine Dose Regimen mg/kg 1 2 3 4 5 6 7 8 9 10 Av Control 4.6 4.6 54.9 5 4.2 4.6 4.9 4.8 4.6 4.72 Vehicle 12 9 14 10.8 10 12 11 10 12 810.88 Colchicine 0.01 10 9 9 12 8 11 11 8 12 8 9.8 0.1 10 7.8 8 9.8 1111 15 9 9 8 9.86 1 7 5.9 8 8.6 5.6 4.6 4 5.2 8 4.4 6.13 Lesinurad 0.1 118 10 9.6 9.2 7 8 12 8 9 9.18 1 13 5 10 12 14 7.8 11.4 7 9.6 7 9.68 10 68 6 9 12 8.4 9 7.5 7 10 8.29 Lesinurad/ 10/0.01 11 9 8 9 5 5 7 4.9 6 8.87.37 Colchicine 10/0.1  7.8 8 5 8 10 7 11 9 9.6 5 8.04 ¹Control = noMSU; ²Vehicle = sterile saline

Step E: White Blood Cell (WBC) Count

Total numbers of white blood cells are shown in the table below (×10⁸)for various doses of Lesinurad and/or colchicine are shown in Table 4and graphically in FIG. 6C, demonstrating:

-   -   Four hours after MSU injection, there are significant amounts of        white blood cells in the air pouch;    -   Colchicine dose-dependently lowered the number of white blood        cells;    -   Lesinurad (0.1, 1 and 10 mg/kg/day) significantly lowered the        number of white blood cells;    -   Lesinurad (10 mg/kg/day) co-administered with colchicine (0.01        or 0.1 mg/kg), did not significantly reduce the number of white        blood cells better than either therapy alone.

TABLE 4 White Blood Cell Count for Various Doses of Lesinurad and/orColchicine Dose Regimen mg/kg 1 2 3 4 5 6 7 8 9 10 Av Control 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.01 0.00 0.00 Vehicle 1.98 1.49 5.88 3.024.05 3.24 0.74 0.33 0.18 2.40 2.33 Colchicine 0.01 3.40 0.63 2.27 0.902.22 2.42 0.69 0.34 0.87 2.72 1.65 0.1 2.60 1.21 0.32 1.27 1.51 0.030.06 0.27 0.41 0.14 0.78 1 3.43 0.32 0.52 0.26 0.35 0.03 0.09 0.26 0.360.01 0.56 Lesinurad 0.1 0.14 2.28 2.75 0.48 0.92 0.03 2.00 0.39 0.140.07 0.92 1 0.68 0.01 0.48 0.54 0.26 1.17 0.34 0.02 0.19 0.44 0.41 100.08 0.16 0.55 1.01 1.02 0.95 0.29 0.90 0.60 0.15 0.57 Lesinurad/10/0.01 0.06 0.03 0.08 1.53 0.09 0.05 0.02 0.25 0.20 0.13 0.24Colchicine 10/0.1  0.21 1.24 0.18 0.50 0.65 0.35 0.41 0.47 0.03 0.040.41

Example 3C In Vivo MSU-Induced Inflammation—Rat Knee Joint Study

The objective of this study was to assess the effect of Lesinurad (dosedorally, 0.1-60 mg/kg QD) in monosodium urate (MSU) crystalinjection-induced inflammation in rats.

Step A: Animals and Animal Care

Male Sprague-Dawley rats weighing 130-200 g from Shanghai SLACLaboratory Animal Co., Ltd., China were unpacked, placed in cages, ahealth inspection performed and a number assigned. Rats were caged ingroups of 3-5 with free access to certified laboratory rodent chow anddrinking water, in environmentally-controlled rooms (20-26° C.; 40-70%in relative humidity), with time-controlled fluorescent lighting systemsproviding 12/12 dark light cycle.

Step B: Method

Rats were randomized into 7 groups on the basis of body weight on Day 1and treated according to the Table 5 below.

TABLE 5 Group Treatment Schedule Dose Knee joint Gp n Treatment mL/kgmg/kg Route Dose/Day injection 1 10 ¹Vehicle 10 — p.o. Day 1-Day 7Saline (Once daily) 2 15 ¹Vehicle 10 — p.o. Day 1-Day 7 ²MSU (Oncedaily) 3 10 Colchicine 1 0.1 p.o. (¹Vehicle); Day 1-Day 6 (¹Vehicle)²MSU s.c. (Colchicine) Day 7 (Colchicine) 4 10 Colchicine 1 0.3 p.o.(¹Vehicle); Day 1-Day 6 (¹Vehicle) ²MSU s.c. (Colchicine) Day 7(Colchicine) 5 15 Colchicine 1 1 p.o. (Vehicle); Day 1-Day 6 (¹Vehicle)²MSU s.c. (Colchicine) Day 7 (Colchicine) 6 15 Lesinurad 10 60 p.o. Day1-Day 7 ²MSU (Once daily) 7 10 Lesinurad & 10 60 p.o. (Lesin urad); Day1-Day 7 (Lesinurad); ²MSU Colchicine s.c. (Colchicine) Day 7(Colchicine)(0.1 mg/kg) ¹Vehicle = sterile water; ²MSU = monosodium urate

Groups 1 and 2 were orally dosed with Vehicle (sterile water) once dailyfor seven days from Day 1. Groups 3, 4 and 5 were orally dosed withVehicle from Day 1 to Day 6, on Day 7 they received colchicineadministered subcutaneously. Groups 6 and 7 were orally dosed withLesinurad once daily for seven days from Day 1; Group 7 also receivedcolchicine administered subcutaneously on Day 7.

Thirty minutes post dosing on Day 7, rats were anesthetized and thediameter and surface temperature of right knee joints were measured.Sterilized MSU crystals (6 mg) suspended in sterile saline (0.05 mL)were injected into a knee joint cavity of the right hind limb of eachrat in Group 2-Group 7. The injection was performed from the anterioraspect of the knee joint, which was slightly extended and flexed.Sterile saline (0.05 mL) alone was injected into Group 1 rats.

Four hours after MSU administration, the rats were anesthetized, thediameter of right knee joints were measured with calipers; surfacetemperature for right knees were measured. Synovial lavage fluid fromthe knee was collected by injecting phosphate buffered saline with 1%BSA (0.2 mL) into the joint cavity, the fluid then collected,centrifuged and the supernatants stored at −80° C.

Step C: Increase in Knee Diameter (mm)

The average increase in knee diameter (mm), which is used as a markerfor MSU-induced knee joint swelling, is shown in Table 6 below forvarious doses of Lesinurad and/or colchicine and graphically in FIG. 7(statistical analysis: One-way ANOVA followed by Dunnett's test),demonstrating

-   -   Four hours post saline injection there was little change in the        knee diameter from the pre-injection time;    -   Increase in knee diameter after MSU injection was about nine        fold compared to saline;    -   Colchicine (0.1, 0.3 and 1 mg/kg) dose-dependently decreased the        MSU-induced increase in knee diameter;    -   Lesinurad significantly decreased the MSU-induced increase in        knee diameter;    -   Lesinurad (60 mg/kg/day) co-administered with colchicine (0.1        mg/kg), did not significantly produce better efficacy than        either therapy alone.

TABLE 6 Increase in Rat Knee Diameter Dose Regimen mg/kg n Av Control 100.11 Vehicle 15 0.91 Colchicine** 0.1 10 0.71 Colchicine*** 0.3 10 0.53Colchicine*** 1 15 0.41 Lesinurad*** 60 15 0.46 Lesinurad/Colchicine**60/0.1 10 0.53 **p < 0.01 vs Vehicle; ***p < 0.001 vs Vehicle

III. Human Clinical Trials Example 4 Phase II Clinical Trial—Gout DoseResponse Study

Purpose: To compare the proportion of subjects whose serum urate (sUA)level is <6.0 mg/dL after 28 days of dosing by treatment group.

Official Title: Randomized, Double-Blind, Multicenter,Placebo-Controlled, Safety and Efficacy Study of Lesinurad VersusPlacebo in the Treatment of Hyperuricemia in Patients With Gout

Experimental dosage form: 200 mg capsule of Lesinurad, with appropriatepharmaceutically acceptable excipients

Condition: Hyperuricemia

Intervention: Lesinurad or Placebo

Study Type: Interventional

Study: Allocation: Randomized

Design:

Control: Placebo Control

Endpoint Classification: Safety/Efficacy Study

Intervention Model: Parallel Assignment

Masking: Double Blind (Subject, Caregiver, Investigator, OutcomesAssessor)

Primary Purpose: Treatment

Primary Outcome Measures: Compare the proportion of subjects whose serumurate (sUA) level is <6.0 mg/dL after 28 days of dosing by treatmentgroup.

Secondary Outcome Measures:

-   -   Evaluate the proportion of subjects with sUA levels <6.0 mg/dL        at each weekly study visit.    -   Evaluate absolute and percent reduction from baseline in sUA        levels at each weekly study visit.    -   Evaluate the percent change in 24-hr urine urate level        (excretion) from baseline to Day 28.    -   Evaluate the incidence of gout flares.    -   Evaluate the safety and tolerability of Lesinurad in subjects        with gout.

TABLE 7 Clinical Study Design Arm Intervention 1 Lesinurad 200 mg qd for28 days 2 Lesinurad 200 mg qd for 7 days followed by 400 mg qd for 21days 3 Lesinurad 200 mg qd for 7 days, followed by 400 mg qd for 7 days,followed by 600 mg qd for 14 days 4 Matching placebo qd for 28 days

Eligibility

Ages Eligible for Study: 18-75 Years

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Inclusion Criteria:

-   -   Male or post-menopausal or surgically sterile female.    -   Hyperuricemic (i.e., screening sUA ≧8 mg/dL).    -   Meets criteria for the diagnosis of gout as per the American        Rheumatism Association (ARA) Criteria for the Classification of        Acute Arthritis of Primary Gout (see Appendix B).    -   Willing and able to give informed consent and adhere to        visit/protocol schedules (informed consent must be given before        the first study procedure is performed).

Exclusion Criteria:

-   -   Classified as an overproducer of urine urate (Cur >6.0        ml/min/1.73 m² 24-hour urine).    -   Consumes more than 14 drinks of alcohol per week (e.g., 1        drink=5 oz [150 ml] of wine, 12 oz [360 ml] of beer, or 1.5 oz        [45 ml] of hard liquor).    -   History or suspicion of drug abuse.    -   Documented history of, or suspicion of, kidney stones.    -   History of rheumatoid arthritis or other autoimmune disease.    -   Confirmed (positive serology to HIV1 and HIV2) or suspected HIV        infection.    -   Positive serology to HCV antibodies (Abs), and/or hepatitis B        surface antigen (HBsAg).    -   History of malignancy, except treated non-melanomatous skin        cancer or cervical dysplasia.    -   History of cardiac abnormalities, including abnormal and        clinically relevant ECG changes such as bradycardia (sinus rate        <45 bpm), complete left bundle branch block (LBBB), second or        third degree heart block, intraventricular conduction delay with        QRS duration >120 msec, symptomatic or asymptomatic arrhythmias        with the exception of sinus arrhythmia, evidence of ventricular        pre-excitation, frequent palpitations or syncopal episodes,        heart failure, hypokalemia, family history of Long QT Syndrome,        and/or family history of sudden death in an otherwise healthy        individual between the ages of 1 and 30 years.    -   Any condition predisposing them to QT prolongation including        pathological Q-wave (defined as Q-wave >40 msec or        depth >0.4-0.5 mV).    -   Any use of a concomitant medication that prolong the QT/QTc        interval within the 14 days prior to Baseline (Day 0).    -   QT interval corrected for heart rate according to Fridericia        (QTcF) >450 msec at Screening or pre-dose at Baseline (Day 0).    -   Uncontrolled hypertension (above 150/95).    -   Inadequate renal function [serum creatinine >1.5 mg/dL or        creatinine clearance <60 mL/min (by Cockroft-Gault formula)].    -   Hemoglobin <10 g/dL (males) or <9 g/dL (females).    -   Alanine aminotransferase (ALT) or aspartate aminotransferase        (AST) >2.5×upper limit of normal (ULN).    -   Gamma glutamyl transferase (GGT) >3×ULN.    -   Active peptic ulcer disease requiring treatment.    -   History of xanthinuria, active liver disease, or hepatic        dysfunction.    -   Requires therapy with any other urate-lowering medication, other        than the study medication.    -   Requires long-term use of salicylates; diuretics; azathioprine;        mercaptopurine; theophylline; intravenous colchicine;        cyclosporine; cyclophosphamide; pyrazinamide; sulfamethoxazole;        or trimethoprim.    -   Taking medications known as enzyme inducers.    -   Gout flare at screening that is resolved for less than one week        prior to the first treatment with study medication (exclusive of        chronic synovitis/arthritis).    -   Pregnant or breast feeding.    -   Received an investigational medication within 4 weeks prior to        study medication administration.    -   Known hypersensitivity or allergy to colchicine or any        components in their formulations.    -   Body mass index (BMI) >40 kg/m².    -   Taking greater than 1000 mg/day of Vitamin C.    -   Any other medical or psychological condition, which in the        opinion of the Investigator and/or Medical Monitor, might create        undue risk to the subject or interfere with the subject's        ability to comply with the protocol requirements, or to complete        the study.

Results: Incidence of gout flares are presented in Table 8 belowindicating the majority of flares occurred in the first week whenpatients were receiving 200 mg QD (6/10 total flares on drug). Fewadditional flares occurred as dose increased, even with greater decreasein sUA. Duration of flares is shorter at higher doses, the opposite ofwhat would be expected with greater reduction in sUA.

TABLE 8 Incidence of Gout Flares % Patients Mean % of patients with MeanRandomized with Duration Flares by Dose at Duration Dose Group N Flaresof Flares Time of Flare of Flares 600 mg 32 13% 1.5 days 9% (3/32) 1.7days   400 mg 33 12% 3.8 days 2% (1/65) 2 days 200 mg 31 6%   4 days 6%(6/96) 4 days Placebo 27 4%  1 day 4% 1 day 

Example 5 Lesinurad Treatment of Gout Patients with Hyperuricemia

A phase II clinical trial including 123 gout patients with hyperuricemia(serum uric acid ≧8 mg/dL) in 4 treatment arms was conducted. The traillasted 8 weeks, comprising a 2 week run in period, 4 week treatmentperiod and 2 week follow-up.

Patients were randomly assigned to arms 1, 2, 3 or 4 and orallyadministered Lesinurad according to Table 9 below and FIG. 8; allreceived colchicine prophylaxis (0.5-0.6 mg QD) for 2 weeks prior toLesinurad dosing and throughout the 4 week treatment period.

TABLE 9 Clinical Study Design Lesinurad dose (mg) Arm n Week 1 Week 2Week 3 Week 4 1 31 200 200 200 200 2 33 200 400 400 400 3 32 200 400 600600 4 27 0 (placebo) 0 (placebo) 0 (placebo) 0 (placebo)

Time to first flare for each arm is given in Table 10 below (indicatingcumulative flare rate).

TABLE 10 Time to First Flare Arm Day 0 Day 7 Day 14 Day 21 Day 28 1 2727 26 25 25 2 31 31 30 28 26 3 33 31 31 29 29 4 (placebo) 32 32 32 29 29

Table 11 below shows the percent of patients experiencing at least onegout flare by week 4 of treatment, calculated based on ITT patientnumber.

TABLE 11 Percent of Patient Experiencing at Least One Gout Flare by WeekFour ARM 4 Wk % Flare 1 10 2 12 3 13 ¹Placebo² 12-22³ ¹Placebo⁴ 34 ¹Datafrom clinical studies APEX (Phase III) and TMX-00-004 (Phase II).²Colchicine 0.6 mg qd, bid, or naproxen 250 mg qd administeredprophylactically. ³Projected based on two times the 2 week flare datafrom TMX-00-004. ⁴TMX-0-004 study had 2 weeks on colchicine 0.6 mg bid,2 weeks off during treatment period.

FIG. 9 shows a plot of the cumulative flare rate for flares from days0-35. In a separate study (see Schlesinger et al EULAR, 2010, AbstractOP 0198, “Efficacy of Canakinumab (ACZ885) in the Prevention of Flaresin Gout Patients initiating Allopurinol Therapy”) allopurinol dosed withcolchicine (0.5 mg QD) resulted in 28% of patients experiencing flares.

1. A method of treating gout comprising co-administration of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, and colchicine to asubject.
 2. The method of claim 1, wherein said method provides greatermean gout flare reduction than co-administration of colchicine and atherapeutic agent that is not a dual inhibitor of URAT1 and aninflammasome.
 3. The method of claim 1, wherein the total dosage ofcolchicine administered during co-administration with2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is at least 50% less thanthe total dosage of colchicine that would be required for a similareffect when co-administered with a therapeutic agent that is not a dualinhibitor of URAT1 and an inflammasome.
 4. The method of claim 1,wherein the amount of time that colchicine is co-administered with2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is at least one week lessthan would be required for a similar effect when colchicine isco-administered with a therapeutic agent that is not a dual inhibitor ofURAT1 and an inflammasome.
 5. A method of reducing monosodium urateinduced inflammation in a subject in need thereof, the method comprisingadministering a pharmaceutical composition comprising a pharmaceuticalagent having both uricosuric and anti-inflammatory activity.
 6. Themethod of claim 5 wherein the pharmaceutical agent is a URAT1 inhibitorwith anti-inflammatory activity.
 7. The method of claim 5 wherein thepharmaceutical agent is2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof.
 8. The method of claim 1wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 750 mg.
 9. Themethod of claim 1 wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 600 mg.
 10. Themethod of claim 1 wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 500 mg.
 11. Themethod of claim 1 wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 400 mg.
 12. Themethod of any of claim 1 wherein the daily dose of2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate,or a pharmaceutically acceptable salt thereof, is about 200 mg.
 13. Themethod of claim 12 wherein the daily dose is administered orally. 14.The method of claim 12 wherein the daily dose is administered in themorning.
 15. The method of claim 12 wherein the daily dose isadministered with food.
 16. The method of claim 12 further comprisingadministration of a second serum uric acid lowering agent.
 17. Themethod of claim 16 wherein the second serum uric acid lowering agent isa xanthine oxidase inhibitor.
 18. The method of claim 16 wherein thexanthine oxidase inhibitor is febuxostat or allopurinol.